1-40312705-C-T

Variant names:

• chr1-40312705-C-T
• rs1983658
• NM_001852.4:c.303+26G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001852.4(COL9A2):​c.303+26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,566,894 control chromosomes in the GnomAD database, including 52,197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6342 hom., cov: 32)
  • Exomes 𝑓: 0.24 (45855 hom.)
• Consequence: COL9A2 NM_001852.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.02
• Publications: 14 publications found

Genes affected

COL9A2 (HGNC:2218): (collagen type IX alpha 2 chain) This gene encodes one of the three alpha chains of type IX collagen, the major collagen component of hyaline cartilage. Type IX collagen, a heterotrimeric molecule, is usually found in tissues containing type II collagen, a fibrillar collagen. This chain is unusual in that, unlike the other two type IX alpha chains, it contains a covalently attached glycosaminoglycan side chain. Mutations in this gene are associated with multiple epiphyseal dysplasia. [provided by RefSeq, Jul 2008]

COL9A2 Gene-Disease associations (from GenCC):

• epiphyseal dysplasia, multiple, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Stickler syndrome, type 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• multiple epiphyseal dysplasia due to collagen 9 anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Stickler syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Stickler syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-40312705-C-T is Benign according to our data. Variant chr1-40312705-C-T is described in ClinVar as Benign. ClinVar VariationId is 258385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.651 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001852.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A2	NM_001852.4	MANE Select	c.303+26G>A		intron	N/A	NP_001843.1	Q14055

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A2	ENST00000372748.8	TSL:1 MANE Select	c.303+26G>A		intron	N/A	ENSP00000361834.3	Q14055
	COL9A2	ENST00000461118.6	TSL:1	n.869+26G>A		intron	N/A
	COL9A2	ENST00000482722.5	TSL:1	n.263+26G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41140 AN: 151948 Hom.: 6320 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.256

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.228

GnomAD2 exomes AF: 0.297 AC: 51972 AN: 175218 AF XY: 0.288

Gnomad AFR exome AF: 0.323

Gnomad AMR exome AF: 0.424

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.663

Gnomad FIN exome AF: 0.253

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.239 AC: 337462 AN: 1414828 Hom.: 45855 Cov.: 34 AF XY: 0.239 AC XY: 166959 AN XY: 699734

African (AFR) AF: 0.325 AC: 10511 AN: 32310

American (AMR) AF: 0.411 AC: 15359 AN: 37396

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 5117 AN: 25300

East Asian (EAS) AF: 0.694 AC: 25792 AN: 37178

South Asian (SAS) AF: 0.258 AC: 20977 AN: 81178

European-Finnish (FIN) AF: 0.253 AC: 12743 AN: 50456

Middle Eastern (MID) AF: 0.177 AC: 1012 AN: 5710

European-Non Finnish (NFE) AF: 0.213 AC: 231220 AN: 1086750

Other (OTH) AF: 0.252 AC: 14731 AN: 58550

GnomAD4 genome AF: 0.271 AC: 41205 AN: 152066 Hom.: 6342 Cov.: 32 AF XY: 0.275 AC XY: 20465 AN XY: 74332

African (AFR) AF: 0.315 AC: 13056 AN: 41476

American (AMR) AF: 0.339 AC: 5181 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 701 AN: 3472

East Asian (EAS) AF: 0.670 AC: 3452 AN: 5156

South Asian (SAS) AF: 0.284 AC: 1369 AN: 4816

European-Finnish (FIN) AF: 0.242 AC: 2556 AN: 10582

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.208 AC: 14123 AN: 67974

Other (OTH) AF: 0.230 AC: 484 AN: 2106

Alfa AF: 0.171 Hom.: 643

Bravo AF: 0.283

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.32
DANN	Benign	0.48
PhyloP100		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1983658; hg19: chr1-40778377; COSMIC: COSV65607267; COSMIC: COSV65607267;